There are substantial epidemiologic, clinical, genetic and experimental evidence that suggested a primary role of plasma lipids and lipoproteins in atherogenesis (Adult Treatment Panel II, Circulation 89:1333-1445 (1994); Havel, R. J., Clin. Exp. Hypertens. 11:887-900 (1989)). Atherogenesis is the process by which lipids accumulate in the intimal lining of arteries leading to the formation of plaques and hardening of the vessel wall or atherosclerosis. Although the exact mechanism leading to atherogenesis is still not well understood, abnormalities of lipid and lipoprotein metabolism, coagulation, hyperinsulinism and glycation all seem to contribute significantly to the process (Bierman, E. L., Arterio. Throm. 12:647-656 (1992)). Hyperlipidemia's characteristics of raised plasma concentrations of triglyceride, raised low density lipoprotein (LDL) cholesterol concentrations, and low concentrations of high density lipoprotein (HDL) cholesterol are known independent risk factors for atherosclerosis and its clinical sequelae, ischemic heart disease or coronary heart disease (Harrison's Principles of Internal Medicine, Eds. Braunwald, E., et al., 11th Edition, McGraw-Hill, 1016-1024 (1988); Reaven, G M, et al., N. Engl. J. Med. 334:374-381 (1996); and Hamsten, A., et al., N. Engl. J. Med. 313:1557-1563 (1985)). Hyperlipidemia in clinical practice, defined by the upper 10 percent of the distribution of plasma lipid levels in a population, i.e., serum cholesterol of 205 mg/dl or higher, serum triglycerides of 200 mg/dl, is usually recommended for treatment (Havel, R. J., et al., N. Engl. J. Med. 332:1491-1498 (1995)). Routine measurements of concentrations of cholesterol and triacylglycerides in the plasma have become widespread in clinical practice which permits the identification of patients with asymptomatic hyperlipidemia. Guidelines are available for diagnosis and monitoring responses to therapy. See Workshop Treatment of Hyperlipidemia, 1996-2 (Lakesmedelsverket, Uppsala, Sweden 1996). Lowering plasma lipid concentrations reduces the amount of atherogenic plaques on the intima of blood vessels (Pathologic Basis of Disease, Eds. S. L. Robbins, et al., 3rd Edition, W. B. Saunders 506-518 (1984); Levine, G. N., et al., N. Engl. J. Med. 332:512-521 (1995)).
A number of disorders are associated with hyperlipidemia, such as uncontrolled diabetes mellitus (insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus) (Bianchi, R., et al., Diab. Nutr. Metabl. 7:43-51 (1994); Welborn, T. A., Aust. NZ J. Med. 24:61-64 (1994)), hypothyroidism, uremia, nephrotic syndrome, acromegaly, obstructive liver disease, dysproteinemia (multiple myeloma, lupus erythematosus) (Harrison's Principles of Internal Medicine, Ed. Braunwald, E., et al., 11th Edition, McGraw-Hill 1016-1024 (1988)). A number of drugs also produce hyperlipidemia, such as oral contraceptives, estrogens, glucocorticoids and antihypertensives. Dietary factors such as increased caloric intake (recent weight gain), consumption of foods high in saturated fats and cholesterol and alcohol intake contribute to the development of hyperlipidemia. Aside from these, primary hyperlipidemia include a family of genetic disorders associated with family histories of hyperlipidemia or xanthomas and pancreatitis.
The administration of somatostatin has been shown to reduce plasma triglyceride concentrations in alloxan diabetic dogs (Martin, C., et al., Life Sci. 35:2627-2633 (1984)), normal humans (Moller, N., et al., Clin. Sci., 75:345-350 (1988); Fukushima, H., et al., Endocrinol. Japan., 32:241-248 (1985)) and acromegalics (Cohen, R., et al., Horm. Metab. Res., 24:397-400 (1992); James, R. A., et al., Diabet. Med. 8:517 (1991). Five distinct somatostatin receptor subtypes have been isolated. While the somatostatin type-5 receptor has been found in various areas of the brain, it has not been found in the major tissues associated with lipid metabolism, such as the liver, pancreas, and muscle. See, Bruno, et al., Endocrinology 133:2561 (1993). The present invention relates to the discovery that the somatostatin type-5 receptor is responsible for this reduction of plasma lipids.